PROJECT SUMMARY/ABSTRACT The overall research goal of this proposal is to determine the contribution of specific genetic events to urothelial squamous metaplasia and bladder tumorigenesis, while developing my technical and professional abilities to become an independent investigator. My professional objective is to acquire a position as an Assistant Professor at a superb academic institution that will enable me to perform cutting edge research on molecular mechanisms responsible for bladder tumorigenesis and bladder cancer progression. In addition, I will continue fostering strong interdisciplinary relationships with urologic surgeons and medical oncologists in an effort to leverage my discoveries to address the most pressing clinical and translational research objectives in bladder cancer research. To achieve these goals, I will engage in research training objectives during the mentored K99 phase of this application. Training activities will include attendance of instructional courses in biostatistical analysis methods and clinical trial design. In addition, I will capitalize on the strengths of Department of Urologic Surgery at VUMC by integrating research training with components of the Urologic Oncology Fellowship program, enabling me to attend multidisciplinary urologic oncology meetings, therefore increasing my exposure to the current state of the art in bladder cancer treatment. Additional career development mechanisms will include instructive seminars at national meetings, mentored guidance in grant and manuscript preparation, and academic job interviewing. In addition, an advisory committee will evaluate the completion of both my scientific and career development milestones and facilitate my transition to an independent investigator. Development of squamous metaplasia and subsequently bladder cancer poses a significant risk to health. Moreover, clinical management of bladder cancer is extraordinarily expensive, and imposes a major fiscal burden in health care expenditure. As the molecular mechanisms resulting in squamous metaplasia and/or bladder tumorigenesis are not completely understood, an increased effort is needed to identify novel molecular targets for the management of this common urologic malignancy. Based on our preliminary studies, I hypothesize that PPAR?-mediated FOXA1 expression maintains normal urothelial differentiation, and combined loss of FOXA1 and PTEN promotes squamous metaplasia and bladder cancer tumor progression in an Akt and/or MAPK dependent manner. The specific aims of this study are as follows: Aim 1: To determine the extent in which PPAR? and FOXA1 loss cooperate with PTEN inactivation to promote PI3K/Akt and MAPK pathway activity in vitro and promote squamous metaplasia and tumor progression in vivo. Aim 2: To determine the extent to which FOXA1 KO cooperates with PTEN deletion to drive squamous metaplasia and urothelial tumorigenesis.